DESCRIPTION: The presence of abnormally functioning estrogen receptor (ER) is postulated to be a major reason why many patients with ER-positive breast cancers fail to benefit from tamoxifen therapy when it is given as first-line therapy for metastatic disease. The applicant has identified a common abnormality in the DNA-binding function of ER isolated from 40% of ER-positive primary breast cancers. The functional defect is recognized as the complete loss of the intact receptor's ability to bind specifically to an ERE in a radiolabelled DNA probe and appears to be due to post-translational chemical modification(s) in the DNA binding domain resulting in altered tertiary or quaternary structure with loss of DNA-binding function. The aims of the proposal are: 1) to verify the clinical significance and utility of the DNA binding assay that detects this abnormality in ER function using two different collections of frozen breast tumor specimens with associated clinical parameters and outcome and 2) to use a newly developed cell culture model that simulates development of this ER defect to characterize the array of potential chemical changes accounting for loss of ER-DNA binding function.